Development and Genetics PSC 113 Jeff Schank

Outline A Brief History of Genetics Gene Expression Genetics and DNA Gene Regulation Hormones and Their Receptors Genes and Gene Families

A Brief History of Genetics How did we get from Mendelian genetics and having no idea about the physical basis of Mendelian factors to modern genetics? Sutton-Bovari Hypothesis (1903): Walter Sutton noticed in a grasshopper species that he was studying that They had 11 chromosome pairs that were morphologically similar

Sutton continued… after meiosis, each gamete had 11 chromosomes offspring have 22 chromosomes or 11 similar pairs He hypothesized that Mendel’s factors were located on chromosomes That is fertilization by the fusion of ovum (11) and sperm (11) restored 22 chromosomes (i.e., 11 pairs) Metaphase II of meiosis FIG. 4 a-o: Meiosis in Brachaspis collinus. (All photographs are of acetic-orcein preparations, x 1000.) (a.) Leptotene: The chromosomes appear as a mass of single threads. The X-chromosome is positively heteropycnotic (arrow). (b.) Zygotene: The nucleus has increased in volume and homologous chromosomes have paired. The X-chromosome is still positively heterochromatic (arrow). (c.) Pachytene: Homologues are separating and each can be seen to consist of two chromatids which are joined at chiasmata, the points of cross-over between non-sister chromatids. (c′.) Interpretation of 4c. Each line represents a chromatid. The eleven bivalents can be individually identified (classification is given). (d.) Mid-diplotene: The bivalents have contracted somewhat and chiasmata are more obvious. (d′.) Interpretation of 4d. The position of the centromeres is indicated by small black circles and the chiasmata by arrows. (e.) Early diakinesis: The bivalents have contracted further and some are beginning to become heterochromatic. (e′.) Interpretation of 4e. (f.) Metaphase I: The bivalents have contracted fully and the autosomes are now heterochromatic. The X is negatively heteropycnotic (arrow). (g.) Anaphase I: Separation of the homologous chromosomes each of which consists of two chromatids joined by the terminal centromere giving a ‘v’ appearance. The X-chromosome has segregated undivided to one pole (arrow). (h.) Telophase I: The ‘v-’ shape of the chromosomes is still apparent. The chromosome number at each pole is n = 11 plus X at one of them. (i.) Interkinesis: A short stage between the two divisions of meiosis. Note that only one cell has an X-chromosome (arrow). (j.) Prophase II: The chromosomes are distinguishable once more and are heterochromatic. (The photographs of meiosis II show the division of only one of the cells formed after meiosis I). (k.) Metaphase II: Chromatids of each chromosome are distinguishable and are still joined at their centromeres (arrows). The chromosome number is n = 11 + X. (l.) Anaphase II: The centromeres have divided and the chromatids have separated to opposite poles. The X-chromosome has also divided. (Some of the chromosomes in this photograph are slightly out of focus.) (m-o.) Spermiogenesis: Differentiation of spermatid nuclei (4m) into spermatids (4n-o). Spermatid nuclei with (arrows) and without an X-chromosome can be seen. Anaphase of meiosis

Thomas Hunt Morgan And his students: Alfred Sturtevant, Calvin Bridges, and Herman Muller, working with fruit flies (Drosophila) were able to show that genes (though they had not been physically identified with DNA) mapped to regions of chromosomes by 1916 they knew genes were parts of chromosomes

Thomas Hunt Morgan Evidence for Linked Genes in Drosophila This figure demonstrates a test cross between flies differing in two characters: body color (b) and wing size (vg). The females are heterozygous for both genes and their phenotypes are wild type, so they display gray bodies and normal wings (b+ b and vg+ vg). The males are homozygous recessive and express the mutant phenotypes for both characteristics, so they display black bodies and vestigial wings (b b and vg vg). When T.H. Morgan scored this particular experiment and classified the offspring according to phenotype, he found that the parental phenotypes were disproportionately represented among offspring. If the two characters were on different chromosomes and assorted independently, Morgan would have expected to see a ratio of recombinant phenotypes to parental phenotypes of 1:1:1:1. Yet Morgan's observation of disproportionate offspring led him to conclude that the genes for body color and wing size in Drosophila were usually transmitted together from parents to offspring because they were located on the same chromosome. Therefore, the black body color gene and the vestigial wing gene are linked. This means that the genetic location for these genes are found close to one another and on the same chromosome. Using Cross Over Frequencies to Map Genes Alfred H. Sturtevant hypothesized that the frequency at which linked genes become unlinked (recombination frequencies; calculated from experiments similar to the one in this figure) could be used to determine the distances between genes on a chromosome. He predicted that the farther apart two genes were on a particular chromosome, the higher the probability that crossing over would occur between them, and subsequently, a higher recombination frequency would be observed.

Gene Expression Genetics and DNA Watson and Crick (1953) proposed a model for the DNA molecule (based in large part on the work of Rosalind Franklin) as a chain composed of two strands of sugar phosphate molecules linked together by chemical bases (adenine, cytosine, thymine, and guanine; ACTG) in a double helix formation

DNA Replication Keep in mind that although DNA is often called a replicating molecule, but it can only do so in specific biochemical contexts.

Transcription and Translation

Gene Regulation Genes express proteins, but there are many ways in which this process can be regulated and influenced Many transcription factors are proteins encoded by other genes, and thus the products of certain regulatory genes can encode and regulate other genes This implies that at the molecular level, gene expression is a multistep process, which can be influenced and regulated at every step!

Gene Regulation…

Hormones and Their Receptors Steroid hormones (e.g., estrogens) pass through the cell’s membrane and join with receptors to affect cytoplasmic processes, and through the cell’s nuclear membrane to affect transcription directly Peptide hormones (e.g., oxytocin and vasopressin) may affect the cellular processes by binding with G protein (guanine nucleotide-binding proteins) receptors and initiating second messenger activities that affect cytoplasmic process and/or nuclear processes

Caenorhabditis elegans (C. elegans)

C. elegans Has 20,470 genes Most mammals have 20,000 to 24,000 genes And yet, mammals (especially humans) are much more complex How can there such differences in complexity with similar numbers of genes?

The Genome as a Network Figure. Gene networks showing inter-relationship between differentially expressed genes in LCL from 3 discordant autistic twin sets using Ingenuity Pathways Analysis software. The over-expressed (red) and under-expressed (green) genes were identified as significant using SAM analysis (FDR = 26.4%) of microarray data across 3 twin pairs. The log2 expression ratio cutoff was set at ± 0.58 and was based upon the mean values for each gene. Genes within this network that have a reported role in nervous system development and function are marked with a "#" symbol and include: ASS, ALOX5AP(FLAP), DAPK1, F13A1, IL6ST, NAGLU, PTGS2, and ROBO1. Gray genes are present but do not meet expression cutoff. Hu et al. BMC Genomics 2006 7:118 doi:10.1186/1471-2164-7-118

Genes and Gene Families Gene families are groups of homologous genes that are likely to have highly similar functions or share similar sequences of DNA From: Demuth, J. P. (2006). The Evolution of Mammalian Gene Families

Gene Gain and Loss in Mammals Distribution of gene gains and losses among mammalian lineages. Numbers in parentheses report number of genes gained or lost on each branch. From: Demuth, J. P. (2006). The Evolution of Mammalian Gene Families

Humans Humans have one of the highest rates of gene family evolution (see Table above) with 20 new gene families Nevertheless, even with a high rate of genetic evolution (relatively speaking), humans evolved from a common ancestor to chimpanzees with only a few hundred gains and losses in genes The most common biological functions of rapidly changing gene families include: immune defense and response transcription, translation brain and neuron development intercellular communication and transport Reproduction metabolism